Alzheimer's disease (AD) is an age dependent disease and may include components of autoimmunity. Amyloid beta (Aβ), a peptide cleavage product of the amyloid precursor protein (APP), is a potentially immunogenic protein which may activate both T-cells and B-cells through their receptors. Some anti-Aβ antibodies have been detected in the blood of AD patients (Gaskin, et al. Human antibodies reactive with beta-amyloid protein in Alzheimer's disease. J Exp Med. 1993 Apr. 1; 177(4):1181-6; Gaskin, et al. Autoantibodies to neurofibrillary tangles and brain tissue in Alzheimer's disease. Establishment of Epstein-Barr virus-transformed antibody-producing cell lines. J Exp Med. 1987 Jan. 1; 165(1):245-50). Anti-Aβ antibody therapy and T-cell treatment have shown benefit in APP mouse models and are being tested in patients (Monsonego & Weiner, Immunotherapeutic approaches to Alzheimer's disease. Science. 2003 Oct. 31; 302(5646):834-8; Morgan, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000 Dec. 21-28; 408(6815):982-5; Ethell, et al., Abeta-specific T-cells reverse cognitive decline and synaptic loss in Alzheimer's mice. Neurobiol Dis. 2006 August; 23(2):351-61. Epub 2006 May 30; Wilcock, et al., Microglial activation facilitates Abeta plaque removal following intracranial anti-Abeta antibody administration. Neurobiol Dis. 2004 February; 15(1):11-20). One classic treatment for autoimmune disease, the injection of Intravenous Immunoglobulin (IVIg), has been reported to reduce cognitive problems in AD patients as well. Current diagnosis involves a series of cognition and/or motor function tests and medical history analysis. Some diagnoses of AD rely on the observation of Aβ and tau pathology in the brain, such as imaging technology designed to detect Alzheimer's plaques and tangles.
A vital part of the immune system's response is its ability to adapt to new challenges. One key feature of adaptive immunity is the presence of a highly diverse repertoire of antibodies (B-cell receptors) and T-cell receptors to identify neo-antigens associated with new immune challenges. This diversity is maintained largely by genetic recombination involving selective inclusion of one of the multiple V, D, and J gene segments of immunoglobulins (BCR) and TCRs within individual B-cells and T-cells, respectively.
TCRs are related to immunoglobulins (BCRs) in that the antigen binding domains are generated by somatic recombination during cell development, which shares high similarity. There are four gene loci for TcR, which undergo recombination during development. Unlike BCRs, the TCRs are mainly cell surface molecules with a single antigen recognition site (Janeway, Travers, Walport, Shlomchik, Immunology. (Garland Publishing, New York, ed. 5th, 2001). Most importantly, however, the TCR recognizes short peptide fragments from pathogens. Perhaps due to the MHC portion of the ligand, somatic hypermutation does not occur in TCR genes. Such mutations might result in the loss of recognition of the ligand (Slifka & Whitton, Functional avidity maturation of CD8(+) T-cells without selection of higher affinity TCR. Nat Immunol. 2001 August; 2(8):711-7). This is consistent with the proposal by Jerne (Jerne, The somatic generation of immune recognition. Eur J Immunol. 1971 January; 1(1):1-9) that the germ line antigen receptors are predisposed to react with MHC molecules.
T-cells produce two different TcRs, the αβTcR and the γδTcR. The αβTcR predominates, and consists of a heterodimer of α and β chains, each coded by different gene products. Both the α and β chain comprise two external Ig-like domains anchored into the plasma membrane by a transmembrane peptide and a short cytoplasmic tail. The heavy chain (variable) domain gene is assembled from a V gene encoding approximately the first 94 residues, which combines with a D (diversity) gene segment and a J (joining) gene segment. The region of the V-D-J junction forms the third hypervariable regions of the V domain, while the first and second hypervariable regions are encoded within the V gene. There are more than 200 V genes in the IgH locus, with 10 D genes and 4 J genes. Since any of the V genes can recombine with any D gene and any J gene, the number of possible combinations of V-D-J is enormous. Light chain genes also undergo recombination, but these loci only contain V and J gene segments, so the third hypervariable region of the light chain is formed at a V-J junction. Recombination of either heavy or light chain genes leads to the loss of the intervening stretches of DNA, containing both introns and exons. Within the T-cell β-chain population, in addition to the diversity generated by the specific V gene fragment included in the TCR, there is internal deletion of portions of the V gene segment, creating length heterogeneity of the V domain in the final TCR. The loci contain VDJ and C gene segments, and somatic rearrangement must occur to generate a functional TcR gene. The rearrangement process generates most of the diverse range of receptors required to mount an effective immune response.
The ability of V, D, and J gene segments to combine together randomly introduces a large element of combinatorial diversity into the Ig and TcR repertoires. The precise point at which V, D, and J segments can join vary, giving rise to local amino acid diversity at the junction. The exact nucleotide position of joining can differ by as much as 10 residues resulting in deletion of nucleotides form the ends of the V, D, and J gene segments. During the rearrangement process additional nucleotides not encoded by either gene segment can be added at the junction between the joined gene segments, called “N-region diversity”.
Motz, et al. reported that cigarette smoke can drive TCR clonality in a tissue specific manner in mice (Motz, et al. Persistence of lung CD8 T-cell oligoclonal expansions upon smoking cessation in a mouse model of cigarette smoke-induced emphysema. J Immunol. 2008 Dec. 1; 181(11):8036-43). Motz also reported that the ‘restricted’ versatility of the TCR in contrast to the BCR might serve a homeostatic function. In this way, the subtly variable T-cells constitute an evolutionary link between the invariable innate and hypervariable B-cell systems. Consistent with this notion, 5-8% of the notoriously heterogeneous neutrophil population (at least 18 subsets) carry a TCR-based variable immunoreceptor (Puellmann, et al. A variable immunoreceptor in a subpopulation of human neutrophils. Proc Natl Acad Sci USA. 2006 Sep. 26; 103(39):14441-6. Epub 2006 Sep. 18). Some of these neutrophils are totally inactive and have strikingly different surface properties (Eggleton, et al. Fractionation of human neutrophils into subpopulations by countercurrent distribution: surface charge and functional heterogeneity. Eur J Cell Biol. 1992 April; 57(2):265-72). Bakács, et al also earlier suggested a model in which a dynamic steady state neutrophil population was achieved by interactions between T-cells and host cells (Bakács, et al. Some aspects of complementarity in the immune system. A bird's eye view. Int Arch Allergy Immunol. 2001 September; 126(1):23-31).
However, the immune system declines with increasing age, starting at around 50 years of age in humans, through immunosenescence. T-cells change in both number and function with the atrophy of the thymus, when T-cells mature. The human immune system maintains a so-called ‘blind homeostasis’ since it senses all CD3 T-cells. As the number of soluble TCRs is reduced due to the destruction of T-cells, more and more membrane-bound pMHC molecules become free. This generates a feedback homeostatic regulatory signal from complementary cells in tissues, which stimulate T-cell production and recruitment. It is also postulated that the peptide recognized by the helper T-cells should be a physical part of the antigen, which is recognized by the B-cell. Such a peptide is produced by the internalization of the BCR-bound antigen (Janeway, Travers, Walport, Shlomchik, Immunology. (Garland Publishing, New York, ed. 5th, 2001). Therefore, both B-cells and T-cells are involved in homeostasis and disease progression.
Current AD diagnosis relies on the observation of Aβ and tau pathology in the brain. Previous biomarker screenings for AD were cross-sectional studies and focused on plasma cytokine levels which are easily affected by acute injury. However, new diagnosis methods for AD, particularly in blood, are desperately needed for early diagnosis and initiation of treatment.